More than half of all human cancers are associated with one or more alterations in the tumor suppressor gene TP53 (1-4). Many premalignant lesions, a subset of malignant clones, and germlines of families prone to cancer are characterized by the presence of one wild-type and one mutant allele of 2P53 (5-9) (See SEQ ID NO:21-32). In this situation the mutant p53 protein may act in a dominant-negative fashion, ultimately leading to loss of heterozygosity and thus a further growth advantage for the malignant cells. Alternatively, the mutant p53 protein may have acquired a new tumor promoting act which is independent of wild-type p53. These hypotheses are based on the analysis of only a few TP53 mutations usually in the setting of over-expression of the mutant protein, and their relevance to TP53 mutations in general has not been proven (8, 10-13).
Absent or significantly reduced activity of the tumor suppressor protein p53 can be due to the presence of abnormally high levels of host proteins, i.e. mdm-2 or viral proteins, i.e. high-risk human papilloma virus E6 (8, 11, 35). However, in the majority of cancers p53 inactivation is caused by missense mutations in one TP53 allele with concomitant loss-of-heterozygosity (8, 10-12, 36. The missense mutations can be further classified into those affecting codons important for contacting the DNA binding sites and structural mutants affecting codons which stabilize the hydrophobic p53 core domain (31-33, 37). The unusually high frequency of TP53 missense mutations in human cancers can be explained by their dominant-negative effect. Interference with the initially still present wild-type p53 allele leads to increased genetic instability, loss-of-heterozygosity and thus complete abrogation of p53 function (10, 11, 38, 39, 40). In addition, there is evidence that at least some of the same missense mutations confer a gain-of-function (35, 40).
Reconstitution of wild-type p53 activity in these cancers could be of large therapeutic benefit (41-47). The anti-tumor effect of reconstituted p53 activity could be further enhanced by utilization of conventional anti-cancer therapies (43, 44, 46). There is a need in the art for means of correcting the abnormalities found in p53 in human cancers.